Inflammatory bowel diseases (IBD), including Crohn's disease (CD) and ulcerative colitis (UC), are chronic inflammatory gastrointestinal disorders commonly thought to predispose to vitamin B12 (cobalamin, Cbl) deficiency. The most important clinical manifestations of Cbl deficiency include nervous system dysfunction and megaloblastic anemia.1–3 Dietary Cbl must bind gastric-derived intrinsic factor (IF) for its absorption in the distal ileum.3 CD can affect any segment of the gastrointestinal tract, whereas UC is confined to colon. One third to half of the patients with CD have isolated ileal disease and 30% to 55% have ileocolonic disease.3–5 Because ileal disease or resection may mediate Cbl malabsorption, patients with CD are assumed to be at greater risk for deficiency.
Aside from ileal disease or resection, other postulated mechanisms for Cbl deficiency in CD include fistulas, small bowel bacterial overgrowth, reduced alimentary intake, increased physiologic requirements, protein losing enteropathy, and hepatic dysfunction.3,6–9 One case study identified gastric CD causing Cbl deficiency, mimicking autoimmune gastritis and subsequent pernicious anemia.10
Several definitions have been employed to describe Cbl deficiency. Isolated low serum Cbl levels differ from biochemical deficiency. Biochemical Cbl deficiency is defined as low serum Cbl levels with confirmatory biomarker elevations (methylmalonic acid [MMA] and homocysteine [Hcy]).11 These biomarker elevations confirm intracellular Cbl deficiency because they are substrates of reactions catalyzed by Cbl. Clinical deficiency is defined as a biochemical deficiency with megaloblastic anemia or neurological symptoms.11–14 The majority of Cbl deficiency is found in asymptomatic individuals without megaloblastic anemia.11 This has been termed subclinical Cbl deficiency but is referred to as isolated biochemical deficiency here.
Clinical deficiency arises from severe malabsorptive diseases such as autoimmune gastritis, which accounts for 94% of clinical deficiency.11–14 Progression of isolated biochemical deficiency to clinical deficiency is rare.15 The causes, clinical course, and public health implications of isolated biochemical deficiency are unclear.11,13,16 It has been suggested that these individuals may never develop symptoms of deficiency.11,13,14,17
Although no gold standard for diagnosing Cbl deficiency exists, the National Health and Nutrition Examination Survey (NHANES) guidelines are favored.11,14,18 These stipulate that the diagnosis of Cbl deficiency in asymptomatic individuals should include 1 biomarker of circulating Cbl (serum Cbl or holotranscobalamin II) and 1 functional biomarker (MMA or Hcy) to confirm intracellular Cbl depletion.11,14 Despite this, serum Cbl alone is still commonly used to screen for deficiency.1,8,19 The sensitivity and specificity of serum Cbl are poor for isolated biochemical deficiency.11,16,20–24 A recent article in the New England Journal of Medicine outlined that false positive and negative rates may approach 50%.25 When measuring serum Cbl, tests and cutoffs vary over time and between centers.11 Furthermore, methodology is frequently suboptimal, leading to diagnostic misclassifications.11 The Schilling's test helps to elucidate whether malabsorption occurs but does not help quantify the effect of this malabsorption on body stores. However, this test has largely disappeared for various reasons and is rarely available.17 Table 1 outlines the NHANES diagnostic criteria and standard cutoff values for Cbl deficiency. The standard lower limit cutoff for serum Cbl is 148 pmol/L.1,11,16 Normal upper limit cutoffs for MMA and Hcy are 270 nM/L11,16 and 15 μmol/L,26,27 respectively. Using these cutoffs, multiple population-based studies demonstrate deficiency rates ranging from 5% to 12%.11
Several treatment options exist in patients with Cbl malabsorption. The daily requirement of Cbl is 2.4 μg.25 To achieve this, injected Cbl has traditionally been used with 10% of injected doses being retained in the body.25 However, high-dose oral treatment has also been shown to be effective.25 Oral Cbl can be absorbed by passive diffusion, even in patients with malabsorption. Oral doses of 1000 μg typically deliver 5 to 40 μg to the body.25,28 Multiple randomized trials compared oral doses of 1000 to 2000 μg daily with parenteral therapy in patients with pernicious anemia, atrophic gastritis, or a history of ileal resection. At 3 to 4 months, both groups had symptom resolution, but oral therapy yielded higher Cbl levels and lower MMA levels than parenteral Cbl.25,29–31
The risk of Cbl deficiency in CD is uncertain, making management decisions difficult. Screening for Cbl deficiency as part of routine follow-up visits for CD is often suggested.6,32–36 Furthermore, suggestions to follow and treat Cbl deficiency in IBD as in autoimmune gastritis have been made.25 These measures may not be justified in all patients. Rather than using NHANES guidelines for diagnosis, gastroenterologists often manage patients with CD with isolated asymptomatic low serum Cbl with prolonged and frequently unjustified parenteral therapy associated with increased time and cost expenditures.37,38
Determining the risk factors for Cbl deficiency in CD is essential to guiding management and understanding risks of clinical sequelae. This systematic review aims to determine the risk of Cbl deficiency in both CD and UC, the specific disease-related risk factors for Cbl deficiency and the optimal management strategy. Definitions of Cbl deficiency employed in current literature were analyzed. Based on current literature, we have suggested an algorithm for evaluation and management of Cbl deficiency in IBD.
Data Sources and Searches
We have performed a systematic search of the Ovid MEDLINE and Ovid Embase databases (Fig. 1). Eligibility criteria for included studies were decided a priori. Two authors (R.B., U.K.) independently judged study eligibility. The search terms “vitamin B12,” “cobalamin,” and “Colitis, Ulcerative/Inflammatory Bowel Diseases/Crohn's Disease” were used as search terms. MESH subheadings were combined using the Boolean operators “AND” and “OR” for full articles published in the English language between 1946 to the first week of March 2013. Additional publications were retrieved from relevant articles. Publications identified as duplicates were excluded. Cases of disagreement were resolved by discussion and joint analysis of articles by 2 reviewers (R.B., U.K.).
Article titles and abstracts obtained from database searches were reviewed to identify those addressing Cbl deficiency in IBD. Articles not pertaining to this topic in the title or abstract were excluded. Case studies, letters, comments, review articles, and studies analyzing patients nil per os or on total parenteral nutrition were eliminated. Data referring to the prevalence, risk factors, clinical significance, evaluation, and management of Cbl deficiency in IBD were extracted from the articles. Data extraction was performed and agreed on by 2 authors (R.B., U.K.).
The search strategy, summarized in Figure 1, revealed 725 articles. An initial 38 articles were retained.2,3,6–9,32,33,36,39–67 Four additional articles were retrieved from references.4,68–70 There was initial disagreement on 3 articles. Two were excluded, because they did not analyze for Cbl deficiency.71,72 One article was ultimately included as Cbl absorption in UC was studied.51 Articles retained included a total of 3732 patients.
This systematic review of Cbl deficiency in CD and UC included studies analyzing both serum Cbl levels and absorption tests.
The parameters used to diagnose Cbl deficiency in IBD differed among studies analyzed. All studies failed to use NHANES diagnostic guidelines. Many diagnosed deficiency by using the lower limit of laboratory reference ranges for serum Cbl without biomarker confirmation of intracellular Cbl depletion.2,3,6,7,36,54–57,65 Others only used absorption testing, namely the Schilling's test, with neither serum Cbl levels nor biomarkers to confirm effects on body stores.32,45–47,60–64,68 Furthermore, differentiation between clinical deficiency and isolated biochemical deficiency was universally unavailable. The latter likely comprised a majority in “deficient” groups because no studies reported symptoms and isolated biochemical deficiency is predominant in the population.11 Isolated serum Cbl levels have poor sensitivity and specificity in this population.11,16,20–24
Despite these discrepancies, current literature can provide meaningful conclusions. Importantly, Cbl within reference range assures that neither clinical nor isolated biochemical deficiency exists in asymptomatic individuals. Low serum Cbl levels, when used alone, are less helpful in the diagnosis of Cbl deficiency. In view of the significant consequences of Cbl deficiency and the physiological plausibility for its causes, recommendations based on current data are needed, but warrant further verification. Conclusions and recommendations stem from studies analyzing serum Cbl, which homogeneously use lower reference range to define deficiency. Studies analyzing only the Schilling's or other absorption tests provide physiologic insight, but are not used to make conclusions. These studies also show that use of absorption tests as a surrogate for Cbl deficiency is prevalent, despite no evidence of effect on body stores.
Prevalence of Cbl Deficiency in CD
Current evidence does not support CD in general to increase the risk for isolated biochemical Cbl deficiency. Table 2 summarizes studies employing serum Cbl to analyze whether CD predisposes to Cbl deficiency. These studies did not show CD to predispose to Cbl deficiency.2,3,7,9,54,57 Studies conflict on average Cbl levels in patients with CD; several studies demonstrate lower average levels,3,6,7,43,54 whereas others do not.2,8,9,57 Although lower average Cbl levels may exist in CD, studies show serum Cbl levels were within normal reference range (207 to 618 pmol/L).2,3,6,7,9,33,43,54,57 One study finds abnormal Cbl levels of 140 pmol/L, however this was similar to controls (152 pmol/L, P = NS).8 UC and healthy control Cbl levels ranged from 257 to 443 pmol/L2,3,6,7,54,57 and 252 to 517 pmol/L,6,7,9,33,43 respectively.
The reported prevalence of Cbl deficiency in CD ranges from 5.6% to 38%.3,6,8,36,40,49,55,57 These studies used serum Cbl and depended on the local definition of population normal Cbl normal range. Certain studies claim Cbl deficiency exists in CD in general but actually refer to specific subgroups.6 One study uses unique definitions, confusing the matter. In this 2008 study, “abnormal” Cbl levels were defined as less than 224 pg/mL, whereas deficiency was defined as less than 180 pg/mL.3 Abnormal Cbl levels were observed in 18.4% of patients with CD as compared with 5% in UC controls. Deficiency existed in only 10.4% of patients with CD not significantly greater than UC controls.
Clinical Significance of Cbl deficiency
Cbl deficiency is rarely associated with anemia in IBD. Most anemia in IBD is attributable to iron deficiency.3,39,58,59 Megaloblastic anemia attributable to Cbl deficiency accounts for 1.5% of all anemia in IBD.58 The neurological sequelae of Cbl deficiency in IBD were never reported systematically.
Risk Factors for Cbl Deficiency in CD
Risk factors for Cbl deficiency in CD were analyzed by using serum Cbl levels alone, absorption tests alone or serum Cbl levels in conjunction with absorption tests.
In patients with CD, surgical resection of the ileum poses the greatest risk for deficiency. Resection length impacts on available Cbl-IF receptors necessary for absorption. Ileal resections greater than 30 cm are associated with Cbl deficiency and abnormal Schilling's tests.32,40–42,45–47,54,60,64,66,68,69 These may also predispose to megaloblastic changes.69 Studies demonstrate that resections less than 20 cm do not cause deficiency34,43,49,56 but are inconsistent with respect to Cbl absorption using the Schilling's test.30,40,42,60,63,70 Studies conflict on the impact of resections between 20 to 30 cm regarding Cbl deficiency40,54,69 and malabsorption.32,47,60,69 Malabsorption with resections greater than 20 cm has been shown using the Schilling's test,32,54,60 at times as severe as autoimmune gastritis.54 Shorter resections may allow retention of enough surface area in the 3-m long ileum73–76 to adequately absorb Cbl and avoid deficiency. Those with resections less than 20 cm retain two-thirds of the distal ileum. Studies analyzing ileal resections are summarized in Table 3.
Location of CD
As the terminal ileum is the natural site of Cbl absorption, it would be expected that ileal CD is associated with Cbl deficiency. Although studies using only serum Cbl conflict on the effect of ileal CD on average serum Cbl concentrations,3,6,9,36,41,55,56,65 they do not implicate ileal CD causing Cbl deficiency.3,6,9 It should be noted that detection of ileal disease in reviewed studies was likely poor. Most neither specify a method of identification nor the extent of ileal disease.3,6,9,36,47,55,56,65 Approximately 50% to 65% of patients with CD have small bowel disease beyond the reach of ileoscopy.77 Isolated small intestinal CD is difficult to diagnose with ileocolonoscopy and contrast radiography,5 while small bowel follow-through is not sensitive in its evaluation.78 Therefore, traditional techniques likely underestimated ileal disease. Two studies used barium enema and small bowel x-ray to determine disease location.63,66
Using the Schilling's test to measure absorption, normal absorption is demonstrated in ileal CD overall.47,63,66 Two studies analyze length ileal disease. They find ileal disease overall does not cause malabsorption, but involvement greater than 30 to 60 cm causes abnormal Schilling's tests.41,47 However, neither deficiency rates nor serum Cbl levels were reported in these studies.
Other Risk Factors
Age and gender were not associated with lower average serum Cbl levels.3,6 However, studies were mainly comprised of nongeriatric populations. No data exist on their effect on absorption in CD. Although Cbl deficiency is thought to be dependent on a depletion of body stores over time, 2 available studies show that duration of disease does not predispose to deficiency.3,6 No data exist on the effect of disease duration on the Schilling's test. Most studies demonstrate abnormal Schilling's tests47,63,64 with greater extent of disease throughout the entire gastrointestinal tract, while one does not.61
In a majority of studies, disease activity is not associated with malabsorption46,61 or lower Cbl levels.2,9 Few contradict this with Schilling's tests62 and serum Cbl levels.67 In a 2008 study, active IBD, but not CD in particular, lowered average Cbl concentrations, without resulting in deficient levels.7 These results, in conjunction with inflammatory parameters3,6 not being associated with lower serum Cbl levels, suggest no association with disease activity and deficiency.
Cbl Deficiency in UC
Studies did not show UC to predispose to Cbl deficiency or lower average Cbl levels. The prevalence of Cbl deficiency and lower average serum Cbl levels in UC are similar to the general population.3,6,53,54,57,65 One study shows lower average Cbl levels in a Chinese Han population with UC in Central China.44 However, average serum Cbl was not in deficiency range.44 It has been demonstrated that end ileostomies do not to alter Cbl levels in IBD.57 Only UC with restorative proctocolectomy (RP) may predispose to deficiency. However, this requires validation because very few studies either analyze or support this. The reason for this finding is unclear, as the majority of the terminal ileum is retained and incorporated in the constructed pouch. Possible explanations include fecal stasis, adaptive mucosal changes, small bowel bacterial overgrowth, and reduced dietary intake.79 Coull et al52 have performed repeated Cbl measurements in a cohort of 171 patients with RP (89% with UC), with 25% of them having low serum Cbl levels using a cutoff of 188 pg/mL. When serial measurements were available, Cbl levels tended to deteriorate over time. Interestingly, 94% of the Cbl deficient patients had normal Schilling's test and no evidence of bacterial overgrowth. The deficiency was effectively corrected with oral supplementation, implying a normal absorptive mechanism.
Suggested Diagnostic and Therapeutic Approach
A literature-based approach to Cbl testing in IBD, adapted from Carmel et al,17 is provided in Figure 2. As described above, recommendations are made based on current literature analyzing serum Cbl levels, but warrant validation in future studies of patients with IBD using NHANES diagnostic guidelines.
Asymptomatic, low risk individuals do not require screening. Low-normal Cbl levels without biochemical deficiency or symptoms do not require further pursuit17 and may be followed up with repeat testing in 1 year. Potential high-risk features for Cbl deficiency in IBD warrant annual serum Cbl screening. These include patients with CD with ileal involvement or resection, patients with UC with RP, anemic patients with relative macrocytosis and those with suspicious neurologic symptoms.
Approach to Low Serum Cbl in IBD
Low serum Cbl levels warrant an evaluation for signs, symptoms, and laboratory parameters (macrocytic anemia) of clinical Cbl deficiency. If present, clinical deficiency is diagnosed. However, the majority of cases are asymptomatic without macrocytic anemia. Here, confirmatory biomarker testing is needed to diagnose isolated biochemical deficiency. If no explanation exists for an isolated biochemical deficiency, the presence of severe Cbl malabsorptive diseases such as autoimmune gastritis or gastric resection should always be sought, regardless of Cbl levels. Furthermore, deficiency in a patient with IBD without ileal involvement or resection should always have other causes of deficiency sought.
Treatment and Prophylaxis in Patients with IBD
Clinical deficiency and severe Cbl malabsorptive diseases necessitate treatment, prophylaxis, and screening. Prophylaxis in severe Cbl malabsorptive diseases is needed (regardless of Cbl levels) because of the inevitability of developing deficiency. In uncertain suspicious cases, therapeutic trials may be justified, regardless of Cbl levels. This includes those with an increasing MCV, any ambiguous symptoms or potential risk factors for malabsorption (e.g., ileal CD). In nonmalabsorbing patients with isolated biochemical deficiency, no treatment is needed. Annual testing should continue until resolution.17 Current literature supports ileal resections greater than 30 cm to be managed as a severe Cbl malabsorptive disease. Uncertainty of 20 to 30 cm resections necessitates management equivalent to 30 cm resections. Resections less than 20 cm and ileal disease have not been associated with Cbl deficiency in CD. While evidence does not indicate a need for treating these patients, given the theoretical risk, a potential underestimation of ileal CD and contradictory studies, further studies are needed. For these uncertain cases, if suspicion of progressive malabsorption exists, a therapeutic trial can be pursued. Patients with CD without ileal disease or resection should be treated equivalently to low risk individuals. Patients with UC with RP may be treated as those with ileal CD. Other patients with UC, including those with end ileostomies, are at low risk to develop deficiency.
Treatment Regimens and Endpoints
If treatment is indicated, an appropriate method of treatment and clear therapeutic endpoints are needed. In clinical deficiency, endpoints of supplementation should be resolution of megaloblastic anemia, improvement in myelopathy, and normalization of serum Cbl and MMA.25 Patients with clinical deficiency or severe Cbl malabsorptive disease should receive 1000 μg of injected Cbl every other day for 1 week, then weekly until clinically improved, followed by monthly injections for life.25 Correction of megaloblastic anemia may take up to 8 weeks. Neurologic dysfunction may transiently worsen and then subside over weeks to months.25 In isolated biochemical deficiency, symptom prevention and maintenance of normal serum Cbl is the aim. Those with ileal resections greater than 20 cm must receive lifelong replacement.25 Injected Cbl is currently the standard treatment. Oral therapy may be as effective,25 but is underexplored in CD. Isolated biochemical deficiency in ileal CD, ileal resections less than 20 cm, or UC with RP may warrant high dose oral Cbl therapy in therapeutic trials.
Genetic Hypotheses in IBD and Cbl Deficiency
Genetic factors may predispose to CD and protect against Cbl deficiency. The FUT2 gene encodes a fucosyltransferase, regulating intestinal antigen secretion and bacterial adherence.80–82 A nucleotide polymorphism encodes a nonsense variant that may contribute to CD by disrupting bacterial adherence or mucin fucosylation.82 This alters bacterial and mucous protection against pathogens, causing immune disequilibrium and mucosal inflammation.80,82 Supporting genome wide association studies strongly associate homozygous mutants, nonsecretion, and CD, but not UC.80,82,83
Genome wide association studies associate mutated FUT2 with increased Cbl levels81 and less Cbl deficiency.80–82 FUT2 mutation, through lack of mucosal carbohydrates, prevents Helicobacter pylori (HP)-mediated gastritis, increasing IF levels and Cbl absorption.80,82 A low HP prevalence in CD and HP’s association with low Cbl support this.81 However, independent of HP, FUT2 mutants have increased IF,84 suggesting other etiologies.
Further studies using NHANES diagnostic guidelines are needed to properly determine the true prevalence of Cbl deficiency in CD across different patient subgroups and assist in management decisions. They are also needed to establish firm diagnostic and therapeutic guidelines. Confirmatory biomarker testing is required when serum Cbl is low, because serum Cbl levels alone are likely insufficient to diagnose deficiency in asymptomatic patients. Based on the currently available literature, CD without ileal resection, regardless of disease location in the ileum, does not increase the risk for Cbl deficiency. Only ileal resections greater than 20 cm in CD predispose to deficiency and warrant treatment. A concept uniformly taught, that ileal CD causes Cbl deficiency, may not be entirely true.
Dr. Alain Bitton will accept full responsibility for the conduct of this study. He has had access to the data and had the decision to publish. All authors accept the final draft of this article submitted.
Author contributions: Literature review: R. Battat, U. Kopylov, A. Szilagyi; data analysis: R. Battat, U. Kopylov, A. Saxena, E. Seidman, A. Bitton; manuscript drafting: U. Kopylov, A. Szilagyi, A. Saxena, D. S. Rosenblatt, M. Warner, T. Bessissow, E. Seidman; advisory role on diagnosis and current data on cobalamin deficiency: D. S. Rosenblatt, M. Warner; advisory role on inflammatory bowel diseases: T. Bessissow, E. Seidman; project design and inception: R. Battat; table and manuscript creation; R. Battat; advisory role in study design: A. Szilagyi; table creation: A. Saxena; project inception: A. Bitton; advisory role on table and manuscript creation: A. Bitton.
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